Nipped-B-like protein (Nipbl), also known as Scc2 or delangin is a protein that in humans is encoded by the NIPBLgene.[1] Nipbl is required for the association of cohesin with DNA and is the major subunit of the cohesin loading complex.[2] Heterozygous mutations in NIPBL account for an estimated 60% of case of Cornelia de Lange Syndrome.[3]
Function
Nipbl is a large hook-shaped protein containing HEAT repeats.[4] Nipbl forms a complex with Mau4 known as the cohesin loading complex or Kollerin.[5] Cohesin is a ring-shaped protein complex responsible for sister chromatid cohesion. Cohesin is also thought to mediate enhancer-promoter interactions and generate Topologically associating domain. As well as mediating cohesion and regulating DNA architecture the cohesin complex is required for DNA repair by homologous recombination. Given that Nipbl is required for cohesin's association with DNA it is thought that Nipbl is also required for all of these processes. Consistently, inactivation of Nipbl results in the loss topologically associating domains[6] and cohesion.[7]
A cohesin-independent function in the regulation of gene expression has also been demonstrated for Nipbl.[8][9]
Clinical significance
Mutations in this gene result in Cornelia de Lange syndrome (CdLS), a disorder characterized by dysmorphic facial features, growth delay, limb reduction defects, and mental retardation.[1] As these mutations are usually heterozygous, CdLS is caused by a reduction in the abundance of Nipbl not a complete loss. Experiments on cells from patients and mice indicate that the reduction is by less than half.[10] It is not known why a reduction in Nipbl expression results in CdLS.
↑Ciosk R, Shirayama M, Shevchenko A, Tanaka T, Toth A, Shevchenko A, Nasmyth K (2000). "Cohesin's binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins". Molecular Cell. 5 (2): 243–54. doi:10.1016/S1097-2765(00)80420-7. PMID10882066.
↑Rohatgi S, Clark D, Kline AD, Jackson LG, Pie J, Siu V, Ramos FJ, Krantz ID, Deardorff MA (July 2010). "Facial diagnosis of mild and variant CdLS: Insights from a dysmorphologist survey". American Journal of Medical Genetics. Part A. 152A (7): 1641–53. doi:10.1002/ajmg.a.33441. PMID20583156.
↑Kikuchi S, Borek DM, Otwinowski Z, Tomchick DR, Yu H (November 2016). "Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy". Proceedings of the National Academy of Sciences of the United States of America. 113 (44): 12444–12449. doi:10.1073/pnas.1611333113. PMID27791135.
↑Nasmyth K (October 2011). "Cohesin: a catenase with separate entry and exit gates?". Nature Cell Biology. 13 (10): 1170–7. doi:10.1038/ncb2349. PMID21968990.
↑Schwarzer W, Abdennur N, Goloborodko A, Pekowska A, Fudenberg G, Loe-Mie Y, Fonseca NA, Huber W, Haering C, Mirny L, Spitz F (15 December 2016). "Two independent modes of chromosome organization are revealed by cohesin removal". p. 094185. bioRxiv094185.
↑Ciosk R, Shirayama M, Shevchenko A, Tanaka T, Toth A, Shevchenko A, Nasmyth K (February 2000). "Cohesin's binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins". Molecular Cell. 5 (2): 243–54. PMID10882066.
↑Zuin J, Franke V, van Ijcken WF, van der Sloot A, Krantz ID, van der Reijden MI, Nakato R, Lenhard B, Wendt KS (February 2014). "A cohesin-independent role for NIPBL at promoters provides insights in CdLS". PLoS Genetics. 10 (2): e1004153. doi:10.1371/journal.pgen.1004153. PMID24550742.
↑van den Berg DL, Azzarelli R, Oishi K, Martynoga B, Urbán N, Dekkers DH, Demmers JA, Guillemot F (January 2017). "Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration". Neuron. 93 (2): 348–361. doi:10.1016/j.neuron.2016.11.047. PMID28041881.
↑Kawauchi S, Calof AL, Santos R, Lopez-Burks ME, Young CM, Hoang MP, Chua A, Lao T, Lechner MS, Daniel JA, Nussenzweig A, Kitzes L, Yokomori K, Hallgrimsson B, Lander AD (September 2009). "Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome". PLoS Genetics. 5 (9): e1000650. doi:10.1371/journal.pgen.1000650. PMID19763162.
